Cardiovascular Responses To Tetraethylammonium In Conscious Rats Under Normotensive And Pharmacologically-Induced Hypertensive Conditions

Laurice Fretwell, Philip Kemp, Julie March, Sheila Gardiner, Jeanette Woolard. Institute of Cell Signalling, University of Nottingham, Nottingham, NG7 2UH, UK.

Tetraethylammonium (TEA) is a potassium channel inhibitor which preferentially blocks large conductance calcium-activated potassium channels (BKCa) at low concentrations (Wallner et al, 1999). These channels have been implicated in vascular control mechanisms in hypertension (Brenner et al, 2000), potentially providing a new target for antihypertensive drugs. TEA has been extensively used in vitro but not in vivo. This study measured the regional haemodynamic responses to TEA in conscious rats under normotensive conditions and during acute hypertension induced by angiotensin (AII) and arginine vasopressin (AVP). We hypothesized that if BKCa channels have a more important cardiovascular role during hypertension, then blockade of BKCa channels with TEA would elicit a larger cardiovascular response in hypertensive compared to normotensive conditions.

Male, Sprague-Dawley rats (350-450g) were anaesthetized (fentanyl and medetomidine, 300 µg/kg i.p. of each) and implanted with pulsed Doppler flow probes, and, at least 10 days later, intravascular catheters (jugular vein, distal abdominal aorta) to measure renal (R), mesenteric (M) and hindquarters (H) vascular conductances (VC). Experiments began 24h after catheterisation and ran over 3 days. On Day 1, responses to i.v. TEA (6 and 20 mg/kg at least 30 min apart) or vehicle (saline, 0.1 mL,) were assessed 90 min after the onset of i.v. infusion (0.4 mL/h) of saline (control) or AII (1 μg/kg/h) plus AVP (0.1 μg/kg/h) to induce hypertension. No substances were given on Day 2. On Day 3, animals given TEA on day 1 were given vehicle, and vice versa.

Under control conditions (n = 8) resting cardiovascular variables (mean ± SEM) were:- HR 340 ± 11 beats/min, BP 109 ± 6 mmHg, RVC 92 ± 8, MVC 79 ± 12, HVC 46 ± 3 (kHz/mmHg)103. Administration of TEA triggered a short-lived tachycardia (30-60 s; +23 ± 11 beats/min; P<0.05 vs. baseline, Friedman’s test) and increase in blood pressure (10 s; +23 ± 4 mmHg; P<0.05 vs. baseline, Friedman’s test), with transient falls in renal and mesenteric vascular conductances (10 s; -22 ± 5 and -20 ± 3 % change, respectively; P<0.05 vs. baseline, Friedman’s test). In AII/AVP-infused rats (n = 8), resting cardiovascular variables were:- HR 290 ± 13 beats/min, BP 166 ± 3 mmHg, RVC 41 ± 6, MVC 28 ± 5, HVC 18 ± 1 (kHz/mmHg)103, and the initial effects of TEA on RVC and HVC were significantly greater (10 s; -35 ± 5, and -48 ± 4 % change, respectively; P<0.05 vs. control integrated responses, Kruskal-Wallis). In addition, there was a later-onset (90-300 s) fall in blood pressure (-16 ± 3 mmHg; P<0.05 vs. baseline, Friedman’s test) accompanied by hindquarters vasodilatation (+56 ± 12 (kHz/mmHg)103; P<0.05 vs. baseline, Friedman’s test).

In conscious rats, TEA elicited different cardiovascular profiles in control and AII+AVP infused rats, potentially indicating diverse roles for BKCa channels in vascular control in the normotensive and hypertensive state.

Wallner et al. (1999) Current Topics in Membranes. 46:117-140.

Brenner et al. (2000) Nature. 407:870-6.

Supported by a University of Nottingham-funded Career Development Fellowship (LF).